Renal Disease Can Reverse in Patients With Diabetic Nephropathy

In several albeit small and preliminary studies now in patients with diabetic nephropathy, glomerular architecture has been shown to be remodeled and kidney disease regressed in response to various strategies. “Fibrosis is the final common pathway in renal disease, and if we can target it we can prevent progression,” said symposium chair and speaker, Giuseppe Remuzzi, MD, at the Ospedali Riuniti in Bergamo, Italy. He added that it is important to define terms carefully: “reversal” is the complete restoration of normal glomerular architecture, whereas “regression” is the decrease in fibrotic content.

Much recent research has focused on how a hormone, bone morphogenic protein-7 (BMP-7), protects the kidney in animal models with simulated human diseases. In 1975, BMP-7 was originally isolated as a soluble factor from bovine bone and was shown to induce ectopic bone formation, Michael Zeisberg, MD, from Harvard Medical School, Boston, Massachusetts, told the conference attendees. Studies by his group and others showed that BMP-7 reverses epithelial mesenchymal transition (EMT) in a mouse model of nephrotoxic serum nephritis. It counteracts TGF-beta 1–induced EMT and reverses chronic renal injury. “The most interesting finding is when we started treatment, at 3 weeks, the original tubular architecture was almost restored,” Dr. Zeisberg said. “Most of the untreated mice died, but all of the BMP-7–treated mice lived.”

BMP-7 inhibited fibrosis in mouse models of liver, heart, and kidney fibrosis. “In all of these studies, the molecule keeps working, which makes you confident that maybe BMP-7 is physiological and might protect us,” said Dr. Zeisberg. Some researchers have speculated that BMP-7 might be a third kidney hormone. In the liver, BMP-7 functions as a novel hormone to facilitate liver regeneration. “The exciting part is when you neutralize the BMP-7, as compared with a control, the normal region of the liver is inhibited,” Zeisberg said.

Several investigators using different animal models have proven that regression of renal fibrosis can be attained, Christos Chatziantoniou, MD, Hôpital Tenon, Pierre et Marie Curie University, Paris, France, added.

“In humans, we have some data that gives hope, but it is not like in the animal model. Are hypertension, vascular inflammation, and fibrosis cascade events leading to end-stage renal disease [ESRD]? Each process is probably a corrective adaptive response,” he said.

In his remarks, Dr. Remuzzi described a paper that, he said, influenced the focus of his medical career. An article in The Lancet in 1979 by Jones et al described how in 9 diabetic patients, progression of renal failure was very different. The patients with the highest rate of decline — a change in GFR of 5 mL/min/month — would need dialysis in about 1 month. But in 2 of the patients, the decline in GFR was so slow — 0.2 mL/min/month — that they would never need dialysis. This raised the question of how the pattern of progression might be shifted, Dr. Remuzzi said.

Regression of diabetic renal disease was observed in a few patients in a small study of diabetic nephropathy patients who had undergone pancreatic transplantation 10 years earlier. Kidney function did not return to pretransplant values, but, as was the case in experimental animals, these patients showed that remodeling of glomerular architecture is possible.

In a subsequent study in nephrotic patients, the Ramipril Efficacy In Nephropathy (REIN) core study, 3 months of proteinuria reduction predicted improved long-term GFR decline at 3 years. Patients who continued on the ACE inhibitor ramipril for another 2 years as part of a follow-up study had up to 1 mL/min/year less GFR decline. Among the 78 patients treated with ramipril, 10 patients showed improved GFR (regression) and never reached ESRD. In another 16 patients, GFR stabilized (remission) or worsened so slowly that ESRD would be delayed beyond the patients’ life expectancies. Patients originally on conventional treatment who switched to ramipril during the follow-up study continued to progress. Risk reduction for ESRD went from 50% in the core study group (18 months) to 300% in the follow-up study (3 to 4 years). This time-dependent amelioration in GFR decline was paralleled by a progressive reduction in urinary protein excretion.

There does not appear to be a “point of no return” when it comes to remission, he noted. In patients with diabetes and very low GFR, there is still some effect with ACE inhibitors. Dr. Remuzzi advises continuing ACE inhibitors while patients are on dialysis as those not on these drugs have a higher mortality. “Our task is to avoid cardiac disease,” he told nephrologists here.

,” Dr. Remuzzi stated that, “The main message is that “you can stabilize renal function with ACE inhibitors, and you can even reverse progression of the disease, so after many years of treatment, GFR will start to improve.

“We have documented in animals that new capillaries are formed, and the kidney has the capacity to repair itself after treatment with these drugs that inhibit the action of angiotensin II. In humans, the message is that nondiabetic nephropathy always has to be treated, even if patients are admitted very late in the course of their disease with very depressed GFR. Even on dialysis, patients need ACE inhibitor treatment, to protect the heart.

“The key in diabetes to protect the patient is to start early,” Dr. Remuzzi added. “If you start when they have overt proteinuria, it is late.” Beginning treatment when patients have microalbuminuria means more will have remission and regression of disease, he added, although the cardiovascular risk remains, given that microalbuminuria is a strong cardiovascular disease risk factor, he noted.

43rd European Reanl Eaaociation (ERA). Presented July 16, 2006.